Alternative Splicing Transcripts of Zebrafish LGP2 Gene Differentially Contribute to IFN Antiviral Response
Alternative Splicing Transcripts of Zebrafish LGP2 Gene Differentially Contribute to IFN Antiviral Response
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斑马鱼 LGP2 基因的选择性剪接转录对 IFN 抗病毒反应有不同贡献
DOI：
10.4049/jimmunol.1701388
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发表时间：
2018-01-15
影响因子：
4.4
通讯作者：
Zhang, Yi-Bing
中科院分区：
文献类型：
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作者：
Zhang, Qi-Min;Zhao, Xiang;Zhang, Yi-Bing
在哺乳动物中，RIG-I样受体（RLR）RIG-I和黑素瘤分化相关基因5（MDA 5）感测胞质病毒RNA，导致IFN抗病毒应答;然而，LGP 2表现出有争议的功能。鱼LGP 2也是如此。在这项研究中，我们报告了三个斑马鱼LGP 2剪接转录，全长LGP 2，和两个截断变体，LGP 2 v1和LGP 2 v2，在IFN抗病毒反应中发挥不同的作用。全长LGP 2的过表达不仅在有限浓度的poly（I：C）存在或不存在的情况下通过RLR途径增强IFN应答，而且通过相对高浓度的poly（I：C）通过参与RLR途径的信号传导因子的功能衰减来抑制IFN应答;然而，LGP 2 v1和LGP 2 v2仅保留抑制作用。一致地，LGP 2而不是LGP 2 v1和LGP 2 v2赋予对鱼细胞针对鲤鱼春季病毒血症病毒（SVCV）感染的保护，并且在有限的表达水平下，LGP 2比RIG-I或MDA 5发挥更显著的保护。进一步的数据表明，在SVCV感染的早期阶段，LGP 2作为正调节剂发挥作用，但随着SVCV在细胞中复制到一定滴度，这导致IFN的更强表达，LGP 2沿着转变为负作用。这些体外结果表明，一个巧妙的机制，三个斑马鱼LGP 2剪接转录协同工作，以塑造IFN抗病毒反应。
In mammals, RIG-I like receptors (RLRs) RIG-I and melanoma differentiation-associated gene 5 (MDA5) sense cytosolic viral RNA, leading to IFN antiviral response; however, LGP2 exhibits controversial functions. The same happens to fish LGP2. In this study we report that three zebrafish LGP2 splicing transcripts, a full-length LGP2, and two truncating variants, LGP2v1 and LGP2v2, play distinct roles during IFN antiviral response. Overexpression of the full-length LGP2 not only potentiates IFN response through the RLR pathway, in the absence or presence of poly(I:C) at limited concentrations, but also inhibits IFN response by relative high concentrations of poly(I: C) through functional attenuation of signaling factors involved in the RLR pathway; however, LGP2v1 and LGP2v2 only retain the inhibitory role. Consistently, LGP2 but not LGP2v1 and LGP2v2 confers protection on fish cells against spring viremia of carp virus (SVCV) infection and at limited expression levels, LGP2 exerts more significant protection than either RIG-I or MDA5. Further data suggest that in the early phase of SVCV infection, LGP2 functions as a positive regulator but along with SVCV replicating in cells up to a certain titer, which leads to a far more robust expression of IFN, LGP2 switches to a negative role. These in vitro results suggest an ingenious mechanism where the three zebrafish LGP2 splicing transcripts work cooperatively to shape IFN antiviral responses.